4.1. Therapeutic indications

Rybrevant subcutaneous formulation is indicated:

• in combination with lazertinib for the first‑line treatment of adult patients with advanced non‑small cell lung cancer (NSCLC) with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations.

• in combination with carboplatin and pemetrexed for the treatment of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI).

• in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations.

• as monotherapy for treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations, after failure of platinum‑based therapy.

4.2. Posology and method of administration

Treatment with Rybrevant subcutaneous formulation should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Before initiation of Rybrevant subcutaneous formulation, EGFR mutation status in tumour tissue or plasma specimens must be established using a validated test method. If no mutation is detected in a plasma specimen, tumour tissue should be tested if available in sufficient amount and quality due to the potential for false negative results using a plasma‑test. Once EGFR mutation status has been established, testing does not need to be repeated (see section 5.1).

Rybrevant subcutaneous formulation should be administered by a healthcare professional with access to appropriate medical support to manage administration‑related reactions if they occur.

For patients currently receiving amivantamab intravenous formulation, Rybrevant subcutaneous formulation may be used as an alternative to the intravenous amivantamab formulation starting at the next scheduled dose.

For patients currently receiving Rybrevant subcutaneous formulation at an every 2-week dosing regimen, an every 4-week dosing regimen may be used as an alternative starting at the next scheduled dose.

Posology

Premedications should be administered to reduce the risk of administration‑related reactions with Rybrevant subcutaneous formulation (see below “Dose modifications” and “Recommended concomitant medicinal products”).

Rybrevant subcutaneous formulation in combination with lazertinib or as monotherapy

The recommended dosages of Rybrevant subcutaneous formulation in combination with lazertinib or as monotherapy, based on baseline body weight, are provided in Table 1 (every 4-week dosing) and Table 2 (every 2-week dosing).

When given in combination with lazertinib, it is recommended to administer Rybrevant subcutaneous formulation any time after lazertinib when given on the same day. Refer to section 4.2 of the lazertinib Summary of Product Characteristics for recommended lazertinib dosing information.

Rybrevant subcutaneous formulation in combination with carboplatin and pemetrexed

The recommended dosages of Rybrevant subcutaneous formulation when used in combination with carboplatin and pemetrexed, based on baseline body weight, are provided in Table 3.

When used in combination with carboplatin and pemetrexed, Rybrevant subcutaneous formulation should be administered after carboplatin and pemetrexed in the following order: pemetrexed, carboplatin and then Rybrevant. See section 5.1 and the manufacturer's prescribing information for dosing instructions for carboplatin and pemetrexed.

Duration of treatment

It is recommended that patients are treated with Rybrevant subcutaneous formulation until disease progression or unacceptable toxicity.

Missed dose

Every 4-week or every 2-week dosing: If a dose of Rybrevant subcutaneous formulation is missed between Weeks 1 to 4, it should be administered within 24 hours. If a dose of Rybrevant subcutaneous formulation is missed from Week 5 onward, it should be administered within 7 days.

Every 3-week dosing: If a dose of Rybrevant subcutaneous formulation is missed between Weeks 1 to 3, it should be administered within 24 hours. If a dose of Rybrevant subcutaneous formulation is missed from Week 4 onward, it should be administered within 7 days.

If the missed dose is not administered according to this guidance, the missed dose should not be administered and the next dose should be administered per the usual dosing schedule.

Dose modifications

Dosing should be interrupted for Grade 3 or 4 adverse reactions until the adverse reaction resolves to ≤ Grade 1 or baseline. If an interruption is 7 days or less, restart at the current dose. If an interruption is longer than 7 days, it is recommended restarting at a reduced dose as presented in Table 4. See also specific dose modifications for specific adverse reactions below Table 4.

If used in combination with lazertinib, refer to section 4.2 of the lazertinib Summary of Product

Characteristics for information about dose modifications.

Administration‑related reactions

Premedications should be administered to reduce the risk of administration‑related reactions with Rybrevant subcutaneous formulation (see “Recommended concomitant medicinal products”). Injections should be interrupted at the first sign of administration‑related reactions. Additional supportive medicinal products (e.g., additional glucocorticoids, antihistamine, antipyretics and antiemetics) should be administered as clinically indicated (see section 4.4).

• Grade 1‑3 (mild‑severe): Upon recovery of symptoms, resume Rybrevant subcutaneous formulation injections. Concomitant medicinal products should be administered at the next dose, including dexamethasone (20 mg) or equivalent (see Table 5).

• Recurrent Grade 3 or Grade 4 (life‑threatening): Permanently discontinue Rybrevant.

Venous thromboembolic (VTE) events with concomitant use with lazertinib

In patients receiving Rybrevant in combination with lazertinib, prophylactic anticoagulants are recommended to be used for the first four months of treatment. Consistent with clinical guidelines, patients should receive prophylactic dosing of appropriate anticoagulants, e.g. low-molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended. Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. For further information about prophylaxis for VTE, see section 4.4.

For VTE events associated with clinical instability (e.g., respiratory failure or cardiac dysfunction), both drugs should be withheld until the patient is clinically stable. Thereafter, both medicinal products can be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation, discontinue Rybrevant or lazertinib. Treatment can continue with either Rybrevant or lazertinib, but not both at the discretion of the treating physician (see section 4.4).

Skin and nail reactions

Prophylactic therapy with oral and topical antibiotics is recommended to reduce the risk and severity of skin and nail reactions in patients receiving Rybrevant. Non‑comedogenic skin moisturiser (ceramide‑based or other formulations that provide long lasting skin hydration and exclude drying agents are preferred) on the face and whole body (except scalp) and chlorhexidine solution to wash hands and feet is also recommended. Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. For further information about prophylaxis for skin and nail reactions, see section 4.4.

If the patient develops a Grade 1‑2 skin or nail reaction, supportive care should be initiated as clinically indicated; if there is no improvement after 2 weeks, dose reduction should be considered for persistent Grade 2 rash (see Table 4). If the patient develops a Grade 3 skin or nail reaction, supportive care should be initiated as clinically indicated, and interruption of Rybrevant subcutaneous formulation should be considered until the adverse reaction improves. Upon recovery of the skin or nail reaction to ≤ Grade 2, Rybrevant subcutaneous formulation should be resumed at a reduced dose. If the patient develops Grade 4 skin reactions, permanently discontinue Rybrevant (see section 4.4).

Interstitial lung disease

Rybrevant subcutaneous formulation should be withheld if interstitial lung disease (ILD) or ILD‑like adverse reactions (pneumonitis) is suspected. If the patient is confirmed to have ILD or ILD‑like adverse reactions (e.g., pneumonitis), permanently discontinue Rybrevant (see section 4.4).

Recommended concomitant medicinal products

Prior to the initial dose (Week 1, Day 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of administration‑related reactions (see Table 5). For subsequent doses, antihistamines and antipyretics are required to be administered. Glucocorticoids should also be re‑initiated after prolonged dose interruptions. Antiemetics should be administered as needed.

SpeSpecial populations

Paediatric population

There is no relevant use of amivantamab in the paediatric population in the treatment of NSCLC.

Elderly

No dose adjustments are necessary (see section 4.8, section 5.1, and section 5.2).

Renal impairment

No formal studies of amivantamab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with mild or moderate renal impairment. Caution is required in patients with severe renal impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above.

Hepatic impairment

No formal studies of amivantamab in patients with hepatic impairment have been conducted. Based on population PK analyses, no dose adjustment is necessary for patients with mild hepatic impairment. Caution is required in patients with moderate or severe hepatic impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above.

Method of administration

Rybrevant solution for injection is for subcutaneous use only.

Rybrevant subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified. See section 6.6 for instructions on handling of the medicinal product before administration.

Inject the required volume of Rybrevant subcutaneous formulation into the subcutaneous tissue of the abdomen over approximately 5 minutes. Do not administer at other sites of the body as no data are available.

Pause or slow delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.

If administering with a subcutaneous infusion set, ensure that the full dose is delivered through the infusion set. Sodium chloride 9 mg/mL (0.9%) solution may be utilised to flush remaining medicinal product through the line.

Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, not intact or within 5 cm around the periumbilical area.

Injection sites should be rotated for successive injections.

4.3. Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

4.5. Interaction with other medicinal products and other forms of interaction

No drug interaction studies have been performed. As an IgG1 monoclonal antibody, renal excretion and hepatic enzyme‑mediated metabolism of intact amivantamab are unlikely to be major elimination routes. As such, variations in drug‑metabolising enzymes are not expected to affect the elimination of amivantamab. Due to the high affinity to a unique epitope on EGFR and MET, amivantamab is not anticipated to alter drug‑metabolising enzymes.

Vaccines

No clinical data are available on the efficacy and safety of vaccinations in patients taking amivantamab. Avoid the use of live or live‑attenuated vaccines while patients are taking amivantamab.

4.6. Fertility, pregnancy and lactation

Women of child‑bearing potential/Contraception

Women of child‑bearing potential should use effective contraception during and for 3 months after cessation of amivantamab treatment.

Pregnancy

There are no human data to assess the risk of amivantamab use during pregnancy. No animal reproductive studies were conducted to inform a drug‑associated risk. Administration of EGFR and MET inhibitor molecules in pregnant animals resulted in an increased incidence of impairment of embryo‑foetal development, embryo lethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, amivantamab could cause foetal harm when administered to a pregnant woman. Amivantamab should not be given during pregnancy unless the benefit of treatment of the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnant while taking this medicinal product, the patient should be informed of the potential risk to the foetus (see section 5.3).

Breast‑feeding

It is unknown whether amivantamab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards. A risk to the breast‑fed child cannot be excluded during this short period just after birth, although IgGs are likely to be degraded in the gastrointestinal tract of the breast‑fed child and not absorbed. A decision must be made whether to discontinue breast‑feeding or to discontinue/abstain from amivantamab therapy taking into account the benefit of breast‑feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of amivantamab on human fertility. Effects on male and female fertility have not been evaluated in animal studies.

4.7. Effects on ability to drive and use machines

Rybrevant may have moderate influence on the ability to drive and use machines. Please see section 4.8 (e.g., dizziness, fatigue, visual impairment). If patients experience treatment‑related symptoms, including vision‑related adverse reactions, affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

4.9. Overdose

There is no information on overdose with Rybrevant subcutaneous formulation and no known specific antidote for overdose. In the event of an overdose, treatment with Rybrevant should be stopped, the patient should be monitored for any signs or symptoms of adverse events and appropriate general supportive measures should be instituted immediately until clinical toxicity has diminished or resolved.